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Set1/COMPASS Repels Heterochromatin Invasion at Euchromatic Sites by Disrupting Suv39/Clr4 Activity and Nucleosome Stability

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Set1/COMPASS Repels Heterochromatin Invasion at Euchromatic Sites by Disrupting Suv39/Clr4 Activity and Nucleosome Stability Downloaded from genesdev.cshlp.org on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Set1/COMPASS repels heterochromatin invasion at euchromatic sites by disrupting Suv39/Clr4 activity and nucleosome stability R.A. Greenstein,1,2 Ramon R. Barrales,3,4,5 Nicholas A. Sanchez,1,2 Jordan E. Bisanz,1 Sigurd Braun,3,4 and Bassem Al-Sady1 1Department of Microbiology and Immunology, George Williams Hooper Foundation, University of California at San Francisco, San Francisco, California 94143, USA; 2TETRAD Graduate Program, University of California at San Francisco, San Francisco, California 94143, USA; 3Department of Physiological Chemistry, Biomedical Center (BMC), Ludwig Maximilians University of Munich, 82152 Martinsried, Germany; 4International Max Planck Research School for Molecular and Cellular Life Sciences, 82152 Martinsried, Germany Protection of euchromatin from invasion by gene-repressive heterochromatin is critical for cellular health and viability. In addition to constitutive loci such as pericentromeres and subtelomeres, heterochromatin can be found interspersed in gene-rich euchromatin, where it regulates gene expression pertinent to cell fate. While heterochro- matin and euchromatin are globally poised for mutual antagonism, the mechanisms underlying precise spatial encoding of heterochromatin containment within euchromatic sites remain opaque. We investigated ectopic heterochromatin invasion by manipulating the fission yeast mating type locus boundary using a single-cell spreading reporter system. We found that heterochromatin repulsion is locally encoded by Set1/COMPASS on certain actively transcribed genes and that this protective role is most prominent at heterochromatin islands, small domains interspersed in euchromatin that regulate cell fate specifiers. Sensitivity to invasion by heterochromatin, surprisingly, is not dependent on Set1 altering overall gene expression levels. Rather, the gene-protective effect is strictly dependent on Set1’s catalytic activity. H3K4 methylation, the Set1 product, antagonizes spreading in two ways: directly inhibiting catalysis by Suv39/Clr4 and locally disrupting nucleosome stability. Taken together, these results describe a mechanism for spatial encoding of euchromatic signals that repel heterochromatin invasion. [Keywords: H3K4 methylation; Set1/COMPASS; facultative heterochromatin; gene orientation; heterochromatin spreading] Supplemental material is available for this article. Received May 8, 2019; revised version accepted October 30, 2019. Heterochromatin is a conserved nuclear ultrastructure and functional environments on each side and countering (Rea et al. 2000) that enacts genome partitioning by re- the intrinsic propensity for heterochromatin to invade pressing transcription and recombination at repetitive se- and silence genes. Major mechanisms of boundary forma- quences and structural elements, as well as genetic tion fall into three broad classes: (1) recruitment of factors information not pertaining to the specified cell fate. that directly antagonize the opposite state (for example, Once seeded at specific sequences (Hall et al. 2002; Jia by removal of state-specific signals on chromatin) (Ayoub et al. 2004; Reyes-Turcu et al. 2011), heterochromatin is et al. 2003; Schlichter and Cairns 2005; Lan et al. 2007; subsequently propagated in cis over qualitatively distinct Trewick et al. 2007; Braun et al. 2011), (2) promotion of regions of the chromosome in a process termed spreading. the original state by either depositing or protecting such Positional regulation of heterochromatin is key to deter- signals (Wang et al. 2013, 2015; Sadeghi et al. 2015; Verrier mining and remembering cell fate decisions. Boundary re- et al. 2015), or (3) structural constraint via recruitment of gions often separate adjacent heterochromatin and DNA-binding proteins that tether heterochromatin re- euchromatin domains, reinforcing the distinct signals gions to the nuclear periphery (Bell and Felsenfeld 1999; 5Present address: Centro Andaluz de Biología del Desarrollo, Universidad © 2020 Greenstein et al. This article is distributed exclusively by Cold Pablo de Olavide de Sevilla-Consejo Superior de Investigaciones Científi- Spring Harbor Laboratory Press for the first six months after the full-issue cas-Junta de Andalucía, Sevilla 41013, Spain. publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). Corresponding author: [email protected] After six months, it is available under a Creative Commons License (Attri- Article published online ahead of print. Article and publication date are bution-NonCommercial 4.0 International), as described at http://creative- online at http://www.genesdev.org/cgi/doi/10.1101/gad.328468.119. commons.org/licenses/by-nc/4.0/. GENES & DEVELOPMENT 34:1–19 Published by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/20; www.genesdev.org 1 Downloaded from genesdev.cshlp.org on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Greenstein et al. Kurukuti et al. 2006; Noma et al. 2006). Despite the varied the processes found in metazoans. Fission yeast form con- modalities used in boundary formation, containment is stitutive heterochromatin marked by H3K9me at centro- not absolute. This is evidenced by the observation that meres, telomeres, and the mating type (MAT) locus. boundaries can be overcome by modest dosage changes Boundary formation occurs at pericentromeric regions in heterochromatin factors (Noma et al. 2006; Ceol et al. and the MAT locus via at least two mechanisms: tether- 2011), which leads to the silencing of genes critical to nor- ing to the nuclear periphery through binding of TFIIIC pro- mal cellular function. teins to B-box element sequences in boundary regions In addition to constitutive heterochromatin found at (Noma et al. 2006) as well as specific enrichment of a centromeres, telomeres, and other repetitive sequences, JmjC domain-containing protein, Epe1 (Ayoub et al. repressed domains also form at additional genomic loca- 2003; Zofall and Grewal 2006; Trewick et al. 2007; Braun tions in response to developmental and environmental et al. 2011), which recruits additional downstream boun- signals (Wen et al. 2009; Zofall et al. 2012; Zhu et al. dary effectors. In addition to these constitutive sites, 2013). These facultative heterochromatin domains are facultative heterochromatin forms at developmentally often embedded in euchromatic regions and silence devel- regulated meiotic genes in regions surrounded by canoni- opmental genes in a lineage-specific manner (Wen et al. cal euchromatin, which are partially dependent on Epe1 2009). Resulting from response to changing stimuli, the for containment (Zofall et al. 2012; Wang et al. 2015). Us- final extent of facultative domains can change over ing the well-characterized MAT locus boundary as a mod- time, expanding to different degrees (Wen et al. 2009) el for euchromatic invasion, we found that active gene and even contracting (McDonald et al. 2011) in genomic units could repel spreading and that this function depends space, though how this is achieved is not well understood. on the H3K4 methylase complex Set1/COMPASS. Set1 is Facultative domain size may be tuned at the level of the the catalytic subunit of COMPASS and is responsible for heterochromatin spreading reaction (Hathaway et al. monomethylation, dimethylation, and trimethylation of 2012) and/or the activities promoting its containment or H3K4 in vivo. It is recruited by RNA polymerase and disassembly. While little is known about the former, sev- forms a characteristic pattern of H3K4 methylation states eral models, beyond those known to operate at constitu- over genes, with H3K4me3 near the transcription start tive boundaries (Guelen et al. 2008; Zofall et al. 2012), site (TSS) and H3K4me2 in the gene body (for review, could be invoked to explain the latter. see Shilatifard 2012). We show that rather than acting as How might euchromatin regulate heterochromatin a global antagonist of spreading, like Epe1 or the histone spreading at facultative sites or respond to its expansion acetyltransferase Mst2 (Wang et al. 2015), Set1 regulates beyond constitutive domains? One of the defining fea- spreading at gene-rich environments such as hetero- tures of euchromatin is the presence of active genes. It is chromatin islands. Set1 does not exert its euchromatin thought that transcription from active genes is incompat- protective function by modulating steady-state transcript ible with heterochromatin formation (Scott et al. 2006). levels. Rather, it acts via two separate mechanisms, both Multiple direct effects of transcription have been pro- dependent on its catalytic activity: (1) the disruption of posed to interfere with heterochromatin assembly. These nucleosome stability and (2) catalytic inhibition of the include nucleosome turnover (eviction) by transcribing sole fission yeast H3K9 methylase Suv39/Clr4, by the polymerase, formation of nucleosome-depleted regions Set1 product H3K4me. This study provides a mechanism at transcriptional units, or steric interference by trans- for the encoding of spatial cues within euchromatin that cription-associated complexes (Noma et al. 2006; Garcia contain heterochromatin expansion. et al. 2010; Aygün et al. 2013). Furthermore, we under- stand that unique molecular signatures characterize eu- chromatin and heterochromatin states and are critical to Results their formation. Heterochromatin is marked by methyla- Genes can function as a barrier
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